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DIURETIC & ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS
Oral diuretic agents include:
- Thiazides (eg, chlorothiazide, hydrochlorothiazide),
- loop diuretics such as furosemide, and
- Potassium-sparing agents such as - spironolactone (aldosterone antagonist) and triamterene.
- Osmotic diuretics, administered by injection, include mannitol.
Diuretic overdose
Most common signs of diuretic overdose include: - vomiting,
- Polyuria and polydipsia
- Depression.
Laboratory changes as electrolyte changes: especially potassium, may shift subsequent
to a large ingestion of a diuretic.
Management
It should include monitoring hydration and electrolytes, with correction as needed
ANGIOTENSIN- CONVERTING ENZYME INHIBITORS (ACEI)
Several angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril, captopril, lisinopril,
benazepril) are used therapeutically to treat hypertension & congestive heart failure.
Sings of overdose:
Hypotension : The primary concern in case of acute ACE inhibitor overdose. If
hypotension is severe, secondary renal damage may result. Onset occurs within a few
hours of exposure, depending on the agent (Extended-release formulations may have a
delayed onset of action).
Other signs : Vomiting, weakness & tachycardia or bradycardia.
Monitoring of BUN and serum creatinine is important, particularly if significant
hypotension is present or if the patient has preexisting renal disease, congestive heart
failure or hypovolemia.
Management
1. Patients should be given adequate IV fluids to maintain a satisfactory blood pressure and
good urine output.
2. Activated charcoal is effective in binding the drug from the GI tract if administered
within 1-2 hr of ingestion.
3. Renal function should be monitored if severe or persistent hypotension develops.
BETA BLOKERS TOXICITY
Epidemiology
Common medications used in the treatment of various cardiovascular, neurologic,
endocrine, ophthalmologic, and psychiatric disorders.
Accidental and intentional toxicity is common.
Selectivity is often lost following large overdoses.
Sotalol is unique among beta-blockers in its ability to block potassium channels.
Sotalol is class III antiarrhythmic drugs.
Sotalol is more often associated with ventricular dysrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes)
Under normal conditions, the heart uses free fatty acids as its primary energy source, but
during times of stress, it switches to using carbohydrates to maintain metabolism.
Inhibition of glycogenolysis and gluconeogenesis reduces the availability of
carbohydrates for use by cells.
Hypoglycemia occurs as a consequence of beta -blocker toxicity, it is actually very rare.
In the presence of adequate glucose stores, euglycemia and hyperglycemia are more
common than hypoglycemia.
Clinical Presentation
Neurologic manifestations include depressed mental status, coma, and seizures.
More lipophilic beta-blockers, such as propranolol, cause greater neurologic toxicity than
the less lipophilic agents.
Seizures can occur but are generally brief, and status epilepticus is rare.
Absorption of regular-release beta -blockers occurs rapidly, often with peak effects
within 1 to 4 hours .
Sustained-release cardiac drugs, it is assumed that symptoms may be delayed >6 hours
after ingestion
Co-ingestants that alter gut function, such as opioids and anticholinergics, may affect
absorption of beta -blockers and subsequent onset of symptoms.
Diagnosis
Cardiac monitoring
ECG
Check glucose, potassium, renal function
Chest x-ray
Treatment
1. General Management
ABCs, protect air way
2. GI Decontamination
Activated charcoal may be of benefit if it can be given within 1 to 2 hours after
ingestion. Multiple dose of activated charcoal therapy following ingestion of
sustained-release -blockers
Use of ipecac syrup is not recommended
Gastric lavage is not routinely used, but may be considered for life-threatening
ingestions when the airway is adequately protected from aspiration.
Whole-bowel irrigation may be beneficial after ingestion of a sustained-release
product.
Treat seizures with benzodiazepines
Ventricular tachycardia: lidocaine
3. Glucagon
Glucagon is a first-line agent in the treatment of acute beta –blocker induced
bradycardia and hypotension.
Effects from an IV bolus of glucagon are seen within 1 to 2 minutes, duration of
action of 10 to 15 minutes.
Due to the short duration of effect, a continuous infusion is often necessary after
bolus administration.
The positive inotropic and chronotropic effects of glucagon may not be
maintained for a prolonged period due to possible tachyphylaxis.
Side effects of high-dose glucagon therapy :
Nausea and vomiting
Esophageal sphincter relaxation
4. Adrenergic Receptor Agonists
The beta -adrenergic receptor agonists—such as norepinephrine, dopamine,
epinephrine, and isoproterenol
The most effective adrenergic receptor agonist may be norepinephrine due to its
ability to increase heart rate and blood pressure.
5. High Dose Insulin
Insulin facilitates myocardial utilization of glucose, the desired substrate during
stress.
The initial dose is regular insulin, 1 unit/kg IV bolus followed by 0.5 to 1.0
unit/kg/h continuous infusion.
0.5 gram/kg bolus of glucose should accompany the initial insulin bolus in a
patient whose serum glucose level is <400 milligrams/dL.
Serum potassium levels may fall during therapy.
Serum potassium level should be monitored.
6. Atropine
A muscarinic blocker, is unlikely to be effective in the management of beta
blocker–induced bradycardia and hypotension,
7. Calcium
Calcium administration is not routinely recommended in beta -blocker overdose,
Calcium for IV administration is available in two forms, gluconate and chloride,
both in a 10% solution. Calcium chloride solution contains three times more
elemental calcium than calcium gluconate solution
Ionized calcium levels should be checked every 30 minutes initially and then
every 2 hours to achieve an ionized calcium level of twice the normal value.
8. Phosphodiesterase Inhibitors (Milrinone, Amrinone)
These agents inhibit the breakdown of cAMP thereby maintaining intracellular calcium levels
9. Cardiac Pacing
May be most beneficial in treating torsades de pointes associated with sotalol
toxaicity.
10. Hemodialysis
Ineffective for lipid soluble agents; may help with water soluble agents such as
atenolol, acebutolol.
CALCIUM CHANNEL BLOCKERS TOXICITY
Overview
Examples: amlodipine, diltiazem, verapamil
Calcium channel blockers account for ~40% of deaths in cardiovascular drug
overdose.
Available in immediate and extended release.
Overdoses of immediate-release characterized by rapid progression to
hypotension,
bradydysrhythmia,
cardiac arrest
Overdoses of extended-release result in delayed onset of dysrhythmias,
shock, sudden cardiac collapse, &bowel ischemia.
Physiology/Pharmacology
Calicum is critical for myocardial contractility and conduction.
Maintains tonic constrictior vascular smooth muscle; contraction of skeletal and cardiac
muscle cells
CCB block calcium channels →→ vasodilation, ↓ myocardial contractility or
altering conduction and pacemaker cells
At toxic levels will also inhibit insulin release from pancreas by blocking Ca channels in
β cells
Clinical features
Onset
The onset of symptoms with standard preparation of CCB is typically within 1-2 hr. of
ingestion.
Slow release preparation, the onset of significant toxicity may be delayed 12-16 hr. with
peak effect after 24 hr.
1. Cardiovascular manifestations
The early sign of toxicity are usually bradycardia, first degree heart block and
hypotension.
This may progress to refractory shock and death without appropriate
intervention
Complication may include myocardial ischemia, & stroke.
2. Hyperglycemia (metabolic manifestation)
3. Neurological (seizures & coma)
4. Other
Pulmonary edema
Renal failure
Nausea & vomiting.
Diagnosis
1. Abnormal finding on blood tests in patients with CCB toxicity include the following:
Hyperglycemia
Hypokalemia
Acidosis
2. ECG, toxicity from CCB blockers may manifest as any of the following:
Bradycardia
2nd and 3rd degree heart block
3. Evidence of organ dysfunction due to shock (e.g increased creatinine)
4. Chest x-ray
5. Echocardiography: evidence of impaired contractility.
Treatment………. Focus on 4 Elements
STABILIZATION - ABCs
DECONTAMINATION
ANTIDOTE(S)
SUPPORTIVE THERAPY
1. Stabilization
Correct immediate life threatening complication (most commonly hypotension and
bradycardia )
Intubation (Atropine)
IV access, fluids
2. GI decontamination
Gastric lavage within 1-2 hr. of ingestion
Activated charcoal within 1 hr. of ingestion
Whole bowel irrigation.
3. Antidote administration
Administration of calcium salts (calcium chloride, calcium gluconate) used to overcome
the cardiovascular effects of CCB.
4. Supportive therapy
Vasopressor Following fluid resuscitation; phenylephrine, dopamine, norepinephrine,
epinephrine. Positive inotropy, chronotropy , vasoconstrictive effects of agents
Glucagon
↑ intracellular cyclic AMP→→ activates calcium channels →→↑ HR
Insulin and Glucose…….. Mechanism is not clear
Not all patients will need glucose, because CCB may cause hyperglycemia
At high doses insulin will actually act as an inotrope ,120-150 units/hr...monitor glucose
Lipid Emulsion Therapy
Lipid surrounds CCB drug molecule Prevents it from binding to calcium channel
Lipid provides readily available energy source for myocardial cells.
Transvenous pacing assists with electrical conduction.
Other Therapies
Methylene Blue ( used in CCB overdose with cardiogenic shock)
Levosimendan (calcium "sensitizer")
Used in sever CHF
Sensitizes calcium channels and promotes influx into cell; increase contractility.
Dialysis
Antiarrhythmic Agents Toxicity
Antiarrhythmic Agents
Antiarrhythmic drugs have been classified based upon a primary mechanism of action:
Class I (Na+ channel blockers ), which is sub-classified into:
IA: includes - Procainamide
- Disopyramide
- Quinidine
IB: includes - Lidocaine
- Mexiletine
- Tocainide
IC: includes - Flecainide
- Propafenone
Class II (β-adrenergic blockers)→ as Beta-adrenergic blockers
Class III (drugs that prolong action potential duration, especially K+ channel
blockers)→ as - Amiodarone
- Bretylium
- Sotalol
Class IV (Ca2+ channel blockers) Calcium channel blockers
Diltiazem & Verapamil
Miscellaneous: Digoxin & Adenosine
Na+ channel blockers (class I)
The primary concern of Na+ channel blocker toxicity is that proarrhythmic effects are seen at
a much higher incidence in those with a previous history of myocardial infarction or with
acute myocardial ischemia. The proarrhythmic effects of these drugs would also be more
prevalent in patients with other cardiac complications.
ClassIA → Procainamide
Signs and Symptoms of Overdose
- Agranulocytosis, granulocytopenia, leukopenia, neutropenia,
- Coagulopathy, hemoptysis
- Anticholinergic toxidrome, confusion, drowsiness, mania
- Hyperthermia, hypotension, myasthenia gravis (exacerbation or precipitation)
- Oliguria, renal failure, respiratory failure
- AV block, torsade de pointes
- Intraventricular conduction delay, junctional tachycardia.
Overdosage /Treatment
1. Airway, breathing, and circulatory support; and ECG monitoring are of the most
importance.
2. Decontamination:
Ipecac (drug used to induce vomiting) within 30 minutes or lavage (within 1
hour)/activated charcoal
3. Supportive therapy:
For hypotension
I.V. fluids or
Parenteral inotrope (If un-response to the above) e.g., norepinephrine 0.1-0.2
mcg/kg/minute.
Concurrent sodium bicarbonate and sodium lactate infusions have been effective in
reversing the drug-induced cardiac toxicity.
4. Enhancement of elimination:
Multiple dosing of activated charcoal may be effective
Hemodialysis or charcoal hemoperfusion are effective in decreasing half-life.
(Note: Forced diuresis or peritoneal dialysis is not effective).
Class III→ Amiodarone
The most common adverse effect of Amiodarone is bradycardia,
Amiodarone may also have cardiotoxic effects by stimulating excessive Ca2+
uptake, especially in the presence of procaine.
Signs and Symptoms of Overdose
Patients should be monitored for several days following ingestion.
Sinus bradycardia, AV block, heart block
Hypotension, chest pain, thrombocytopenia
Hyperthyroidism, hypothyroidism, sweating, syncope
Delirium, insomnia, myopathy
Extension of pharmacologic effect, hemoptysis, cirrhosis
Photosensitivity, pseudotumor cerebri, toxic epidermal necrolysis
Admission Criteria/Prognosis
Admit any patient with ECG abnormalities or any adult ingestion > 3 g.
Toxic effects can be observed at levels >2.5 mg/L for parent compound or 1.5 mcg/mL for
desethylamiodarone.
Overdosage/Treatment
1. Decontamination
Lavage (within 1 hour)/activated charcoal;
Cholestyramine can also decrease absorption.
2. Supportive therapy:
Atropine can be used to treat bradycardia (atropine resistant bradycardia has been
reported). ↓ In case of the resistance
Injectable isoproterenol or a temporary pacemaker may be required.
(ECG monitoring is necessary with amiodarone overdose).
3. Corticosteroids may be useful to treat amiodarone pulmonary toxicity; corticosteroid
therapy can be used to treat amiodarone- induced pleural disease.
4. Propylthiouracil (with lithium) has been used to treat amiodarone-induced thyrotoxicosis
with normalization of T4 levels within 5 weeks.
5. Angiotensin amide may be useful in treating hypotension due to amiodarone toxicity.
6. Acetazolamide (125-250 mg twice daily) for Amiodarone-induced ataxia.